We propose to study in open-chest, anesthetized dogs, some of the factors that affect the rates of release and reuptake of norepinephrine at the cardiac sympathetic terminals. We shall measure the changes in heart rate, myocardial contractile force, and coronary blood flow during and after a train of stimuli to the cardiac sympathetic nerves. These cardiac responses will be correlated with the changes in the rate of norepinephrine overflow into the coronary sinus blood. The relative roles played by the amine uptake processes and by diffusion of neurotransmitter into the coronary circulation will be compared at certain specific sites in the heart, notably in the ventricular myocardium and in the S-A nodal region. In different experiments, specific drugs will be employed to block the presynaptic alpha-receptors, the neuronal amine uptake process, or the extraneuronal amine uptake process. As examples of the roles played by these various mechanisms, we shall test several hypotheses to account for the observations that (1) the chronotropic responses to sympathetic stimulation are much more prolonged than are the inotropic responses, when the neuronal uptake mechanism is blocked, and (2) the responses to exogenously administered norepinephrine are potentiated after neuronal uptake blockage, whereas the responses to endogenously released norepinephrine are not potentiated. We shall also investigate whether the chronotropic effects of neuronal uptake blockers are specific for sinus node pacemaker cells, or whether they have similar effects on other cardiac automatic centers, such as those in the A-V junction.